The production of myelin, the ensheathing membrane that is essential for normal brain development and function, is tightly regulated. Bidirectional interactions between axons and myelinating glia determine the amount of myelin that is generated. Intracellular signals must direct the necessary increase in myelin gene expression required for proper myelination and also establish when the ensheathing cell should decrease myelin production and shift to myelin maintenance. Akt signaling has been demonstrated to drive myelination in both the peripheral and central nervous systems. The regulation of central nervous system (CNS) myelination, however, is not well understood. The current proposal investigates the signaling mechanisms that regulate CNS myelination. We will focus on the inhibitory signals that downregulate normal myelination after axons have been appropriately wrapped. In this regard, we propose to investigate the role of negative regulators of Akt signaling in oligodendrocytes, the myelinating cells of the CNS. We will focus on the protein tyrosine phosphatase Shp2, which may act as a brake to active myelination. We will also examine the role of Shp2 during remyelination, the regenerative process of restoring myelin to axons after a demyelinating injury. For these studies, we will utilize transgenic Cre/lox mouse technology in order to induce the knockout of Shp2 specifically in oligodendrocytes. Having a more precise understanding of the signaling mechanisms regulating myelination could help to facilitate the design of more effective treatments for acquired myelin diseases, such as multiple sclerosis.